A synthetic glycolipid prevents autoimmune encephalomyelitis by inducing TH2 bias of natural killer T cells

Experimental autoimmune encephalomyelitis (EAE) is a prototype autoimmune disease mediated by type 1 helper T (T H 1) cells and under the control of regulatory cells 1 , 2 , 3 . Here we report that a synthetic glycolipid ligand for CD1d-restricted natural killer T (NKT) cells expressing the semi-invariant T-cell receptor (Vα14 + ) is preventive against EAE. The ligand is an analogue of α-galactosylceramide (α-GC), a prototype NKT cell ligand, with a truncated sphingosine chain. α-GC causes NKT cells to produce both interferon (IFN)-γ and interleukin (IL)-4 (refs 4 , 5 ). However, this new ligand can induce a predominant production of IL-4 by the NKT cells. A single injection of this glycolipid, but not of α-GC, consistently induced T H 2 bias of autoimmune T cells by causing NKT cells to produce IL-4, leading to suppression of EAE. The lack of polymorphism of CD1d and cross-reactive response of mouse and human NKT cells to the same ligand 6 indicates that targeting NKT cells with this ligand may be an attractive means for intervening in human autoimmune diseases such as multiple sclerosis.